5β-Hydroxy-Δ6 -steroids and process for the preparation thereof

ABSTRACT

The disclosure concerns 5β-hydroxy-Δ 6  -steroids of the general formula ##STR1## wherein R 1  is hydrogen, acyl, lower alkyl, or the tetrahydropyranyl residue and 
     R 2 , R 3  individually are respectively hydrogen or jointly are methylene and 
     X stands for oxygen, the groupings ##STR2## (wherein R 4  means hydrogen or acyl) and ##STR3## (wherein R 5  means hydrogen or lower alkyl) and a process for the preparation thereof by reacting corresponding 7α-chloro-5β,6β-epoxy steroids in an inert solvent with metallic zinc in a lower aliphatic carboxylic acid or dilute mineral acid at temperatures of between room temperature and 100° C., preferably at 40°-70° C. 
     The compounds producible by this method are intermediates for the preparation of 3-keto-Δ 4  -6β,7β-methylene steroids constituting pharmacologically valuable compounds, for example aldosterone antagonists.

BACKGROUND OF THE INVENTION

The invention relates to the subject matter of the claims.

It is known that3β-acetoxy-5-hydroxy-5β,17α-pregn-6-ene-21,17-carbolactone can beprepared from 3β-acetoxy-5,6β-epoxy-5β-pregnane-21,17-carbolactone viathe intermediate stage of3β-acetoxy-5-hydroxy-6α-phenylseleno-5β-pregnane-17,21-carbolactone[Helv. Chim. Acta 62: 2276(1976)].

This process has the disadvantage, however, that highly toxicorganoselenium compounds, such as, for example, diphenyldiselenide, arerequired for the synthesis, the handling of these compounds presentingdifficulties on an industrial scale; disposal of the wastes of thesecompounds can only be made in special dumps, and furthermore thesecompounds are not likely to be available as a raw material in abundantamounts.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide a wayfor producing 5β-hydroxy-Δ⁶ -steriods without the use of selenium.

This object has been attained by the process as characterized in theclaims.

DETAILED DISCUSSION

Acyl is understood to mean acid residues of up to 12 carbon atoms andderived from acids customarily used in steroid chemistry foresterifications. Preferred acids are carboxylic acids of 1-8 carbonatoms. The carboxylic acids can also be branched, polybasic, orsubstituted in the usual way, for example by a hydroxy or amino group.Also suitable are cycloaliphatic, aromatic, mixed aromatic-aliphatic, orheterocyclic acids. Preferred acids for the formation of the acylresidueare, for example, acetic acid, propionic acid, caproic acide,trimethylacetic acid, cyclopentylpropionic acid, cyclohexylacetic acid,phenylpropionic acid, phenylacetic acid, dialkylaminoacetic acid,piperidinoacetic acid, succinic acid, and benzoic acid.

Alkyl is understood to mean residues derived from aliphatic hydrocarbonsand exhibiting 1-6 carbon atoms, such as, for example, methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, and tert.-butyl.

The compounds producible according to the invention are intermediatesfor the preparation of 3-keto-Δ⁴ -6β,7β-methylene steroids representingpharmacologically valuable compounds.

The process of this invention is conducted by dissolving the7α-chloro-5β,6β-epoxy steroid in an inert protonic solvent and stirringthe solution with metallic zinc, for example in pulverized or granularform or in the form of filings, in the presence of an aliphaticcarboxylic acid or a dilute mineral acid at between room temperature andabout 100° C.

Suitable inert protonic solvents are all those which do not react withthe reactants. Examples are aliphatic alcohols, such as methanol,ethanol, n-propanol, and isopropyl alcohol; aliphatic and cycloaliphaticethers, such as diisopropyl ether, tetrahydrofuran, and dioxane, as wellas water.

Besides acetic acid, which is preferably employed, formic acid andpropionic acid are likewise suitable as aliphatic carboxylic acids forconducting the reaction of the invention. However, the use of a dilutemineral acid is also possible, such as hydrochloric acid or sulfuricacid.

The acid utilized is employed in excess. The excess amount is 30-100times the quantity (mol equivalents). The acid is suitably used in aconcentration of 0.2-1.0 mole/liter.

The reaction mixture is heated, a temperature range of 40°-70° C. beingpreferred.

The duration of the reaction is about 0.5-7 hours, this time beingdependent on the starting material employed and especially on thetemperature.

The course of the reaction according to the invention was surprisingsince, under the reaction conditions applied (acidic, temperature aboveroom temperature), it would have to be expected that the thus-formed5β-hydroxy-Δ⁶ - steroids would be converted by allyl rearrangement intocorresponding secondary products. For it is known from the workperformed by Morand [P. Morand and A. van Tongerloo, Steroids 21: 47-61(1973)] that 5-hydroxy-Δ⁶ -steroids are converted even at roomtemperature, in the presence of 80% acetic acid, into the correspondingallyl rearrangement products, such as 7-hydroxy- and 7-acetoxy-Δ⁵-steroids. Moreover, it is known from this work that, in part, evenpolyenes are formed when heating 5-hydroxy-Δ⁶ -steroids with 80% aceticacid.

Using the intermediate product prepared according to this invention,3β-acetoxy-5-hydroxy-15β,16β-methylene-5β-androst-6-en-17-one, theconventional6β,7β,15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone,which has an aldosterone-antagonistic effect, can be prepared, forexample, in the following way:

A solution of3β-acetoxy-5-hydroxy-15β,16β-methylene-5β-androst-6-en-17-one in 300 mlof methanol is stirred with 15 g of potassium carbonate for 30 minutesat room temperature. The reaction solution is diluted with diethylether, washed with water, dried, and evaporated, thus obtaining 27 g of3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one, mp 187°-190°C., (acetone).

A solution of 26 g of3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one in 520 ml ofethylene glycol dimethyl ether is stirred with 78 g of zinc-copper and69 ml of methylene iodide for 4 hours at 80° C. The mixture is thendiluted with methylene chloride, washed with saturated ammonium chloridesolution and water, dried, and evaporated. The residue ischromatographed on silica gel, thus obtaining 16.3 g of3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androstan-17-one, mp205.5°-207° C.

A solution is prepared from 25.1 g of3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androstan-17-one and 500 mlof tetrahydrofuran. Under cooling to 0° C. and an argon atmosphere, 75.5g of potassium methylate is added to this solution and the latter isthen combined dropwise under agitation with 50.4 ml of propargyl alcoholdissolved in 104 ml of tetrahydrofuran. The reaction mixture is stirredat 0° C. for 20 hours and poured into ice water. After neutralizing withdilute sulfuric acid, the thus-obtained precipitate is filtered off anddried. The crude product is chromatographed on silica gel, thusobtaining 25 g of17α-(3-hydroxy-1-propynyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,15β-triol,mp 202°-203° C. (acetone).

24.5 g of17α-(3-hydroxy-1-propynyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triolis hydrogenated in 250 ml of tetrahydrofuran and 125 ml of methanol inthe presence of 3.75 g of palladium on carbon (10%) and 0.5 ml ofpyridine until 2 equivalents of hydrogen have been absorbed. The mixtureis filtered off from the catalyst and evaporated, thus producing 24.7 gof17α-(3-hydroxypropyl)6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triolwhich is used in the subsequent stage without further purification.

A solution of 24.7 g of17α-(3-hydroxypropyl)6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triolin 247 ml of pyridine is combined with a solution of 74.1 g of chromium(VI) oxide in 247 ml of water and 494 ml of pyridine and stirred for 16hours at 50° C. Thereafter the mixture is diluted with methylenechloride, washed with water, dried, and evaporated. The residue ischromatographed on silica gel. Recrystallization from diisopropylether-acetone yields 14.5 g of6β,7β;15β,16β-dimethylene3-oxo-17α-pregn-4-ene-21,17-carbolactone, mp196.5°-197.5° C.

UV: ε₂₆₅ =18,700 (methanol).

Starting with3β,5-dihydroxy-15β,16β-methylene5β,17α-pregn-6-ene-21,17-carbolactone asthe intermediate prepared according to the invention, the same6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone isobtained, for example, by the following method:

A solution is prepared from 5 g of3β,5-dihydroxy-15β,16β-methylene-5β,17α-pregn-6-ene-21,17-carbolactoneand 100 ml of tetrahydrofuran and combined with 15 g of zinc-copper.Within 7 hours, 13.2 ml of methylene iodide is added dropwise to themixture in such a way that the temperature does not rise above 30° C.,and the mixture is agitated for another 10 hours at room temperature. Toremove the metal, the mixture is filtered over "Celite", the filtrate isdiluted with methylene chloride and washed with saturated ammoniumchloride solution, dried over magnesium sulfate, and evaporated undervacuum. The residue is chromatographed on silica gel, thus obtaining 4.4g of3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β,17α-pregnane-21,17-carbolactoneas an oil.

A solution is prepared from 2.8 g of3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β,17α-pregnane-21,17-carbolactoneand 28 ml of pyridine and combined with a solution of 15 g ofchromium(VI) oxide in 28 ml of pyridine and 14 ml of water. The mixtureis stirred for 16 hours at 50° C. After cooling, the mixture is dilutedwith methylene chloride, washed with water, dried over magnesiumsulfate, and concentrated under vacuum. The residue is chromatographedon silica gel, thus obtaining 2.3 g of6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone, mp198°-198.5° C.

The following examples are to explain the process of this invention.

EXAMPLE 1

A solution of 21 g of3β-acetoxy-7α-chloro-5β,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstanein 105 ml of tetrahydrofuran, 105 ml of acetic acid, and 27 ml of wateris combined with 63 g of zinc dust and stirred for 1.5 hours at 80° C.The mixture is then decanted off from the zinc, washed with methylenechloride, and the organic phase is washed with sodium bicarbonatesolution and water. After drying and evaporation, the residue ischromatographed on silica gel, thus obtaining 13.8 g of3β-acetoxy-5-hydroxy-15,16β-methylene-5β-androst-6-en-17-one, mp191°-194° C.

The starting material was produced as follows:

(A) A solution of 95 g of3β-hydroxy-15β,16β-methylene-5-androsten-17-one in 190 ml of pyridinewas combined with 95 ml of acetic anhydride and stirred for 1.5 hours at95° C. The precipitate obtained after pouring the mixture into ice waterwas filtered off, washed thoroughly with water, and dried, thusobtaining 107 g of 3β-acetoxy-15β,16β-methylene-5-androsten-17-one as acrude product. A sample extracted by boiling with diisopropyl ethermelted at 140.5°-141° C.

(B) A solution of 105 g of3β-acetoxy-15β,16β-methylene-5-androsten-17-one in 1.05 l of methylenechloride was combined with 315 ml of ethylene glycol, 210 ml of triethylorthoformate, and 10.5 g of p-toluene-sulfonic acid and agitated for 1hour at room temperature. The reaction solution was combined with 40 mlof pyridine and diluted with ether, then washed with water, dried, andevaporated. The residue was triturated with pentane and vacuum-filtered,thus producing 109 mg of3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androstene, mp177°-178.5° C.

(C) Under agitation, 600 ml of methylene chloride, cooled to -20° C.,was combined in succession with 81 g of chromium(VI) oxide, dried overphosphorus pentoxide, and 84 g of 3,5-dimethylpyrazole. The mixture wasstirred for 30 minutes, combined with 23.2 g of3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androstane, andstirred for 4 hours at -10° C. Subsequently, the reaction solution wascombined with 342 ml of 5N sodium hydroxide solution, stirred for 1 hourat 0° C., combined with 120 ml of diethyl ether, and stirred for another30 minutes. The aqueous phase was separated and the organic phase washedwith water, dried, and evaporated. The residue was chromatographed onsilica gel, thus producing 17.2 g of3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7-one, mp193°-197° C.

(D) 31 g of3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7-one wasreacted at room temperature within 1.5 hours in 310 ml oftetrahydrofuran with 31 g of lithium tri-tert.-butoxyaluminohydride. Thereaction solution was diluted with diethyl ether, washed withpotassium-sodium tartrate solution and water, dried, and evaporated. Theresidue was chromatographed on silica gel, thus obtaining 24.3 g3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7β-ol, mp199.5°-200° C. (acetone).

(E) A solution of 23.3 g of3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7β-ol in350 ml of toluene was combined dropwise, after adding vanadium(IV) oxideacetylacetonate, within 35 minutes with 23.3 ml of 80% tert.-butylhydroperoxide, dissolved in 115 ml of toluene. The reaction solution wasmaintained at 80° C. for another 30 minutes, then cooled, diluted withdiethyl ether, washed with sodium bisulfite solution, sodium bicarbonatesolution, and water, and dried and evaporated, thus obtaining 24.5 g of3β-acetoxy-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstan-7β-ol,mp 162°-163° C. (diisopropyl ether).

(F) A solution of 24 g of3β-acetoxy-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstan-7β-olin 48 ml of pyridine and 48 ml of carbon tetrachloride was combined with28 g of triphenylphosphine and stirred for 1.5 hours at roomtemperature. The reaction mixture was diluted with methylene chloride,washed with water, dried, and evaporated. The residue waschromatographed on silica gel, thus producing 21.5 g of3β-acetoxy-7α-chloro-5,6β-epoxy-17,17-ethylenedioxy-15.beta.,16β-methylene-5β-androstane,mp 169°-170° C. (diisopropyl ether).

EXAMPLE 2

200 mg of17β-acetoxy-3β-benzoyloxy-7α-chloro-5,6β-epoxy-15.beta.,16β-methylene-5β-androstaneis stirred in 4 ml of acetic acid and 4 ml of propan-2-ol with 800 mg ofzinc dust for 1 hour at 80° C. The mixture is filtered off from thezinc, washed with diethyl ether, and worked up analogously to Example 1.After chromatography and recrystallization from diisopropylether-acetone, 135 mg of17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5β-androst-6-en-5-ol isobtained, mp 212°-212.5° C.

Preparation of starting material

(A) A solution of 5.0 g of3β-hydroxy-15β,16β-methylene-5-androsten-17-one in 50 ml of pyridine wascombined under ice cooling with 5 ml of benzoyl chloride and thenstirred for 17 hours at room temperature. After the addition of 10 ml ofwater, the mixture was stirred for another hour; then the reactionsolution was diluted with methylene chloride and washed with sodiumcarbonate solution and water. After drying and evaporation, the residuewas triturated with diisopropyl ether and vacuum-filtered, thusobtaining 6.4 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17-one,mp 250°-258° C.

(B) 6.4 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17-one wasstirred in 64 ml of tetrahydrofuran with 6.4 g of lithiumtri-tert.-butoxyaluminohydride for 1 hour at room temperature. Thesolution was then diluted with ether, washed with 2N sulfuric acid andwater, dried, and evaporated, yielding as the residue 6.5 g of3β-benzoyloxy-15β,16β-methylene-5-androsten-17β-ol, used without furtherpurification in the subsequent stage.

(C) 6.5 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17β-ol, 13 mlof acetic anhydride, and 26 ml of pyridine were heated for 1.5 hours to95° C. After ice water precipitation, the sediment was filtered off andtaken up in methylene chloride. The solution was washed with water,dried, and evaporated, thus obtaining 6.9 g of crude17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androstene, used withoutfurther purification in the next stage.

(D) 6.9 g of 17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androstenewas combined with 69 ml of carbon tetrachloride with an acetictert.-butyl chromate solution prepared from 10.35 g of chromium(VI)oxide, 90 ml of carbon tetrachloride, 28.2 ml of tert.-butyl alcohol,37.2 ml of acetic acid, and 134 ml of acetic anhydride. The reactionsolution was then stirred for 32 hours at 80° C., diluted with methylenechloride, and washed with sodium acetate solution, sodium bicarbonatesolution, and water. After drying and evaporation, the resultant residuewas chromatographed on silica gel, thus obtaining 4.4 g of17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androsten-7-one, mp245°-246° C. (acetone-diisopropyl ether).

(E) The thus-produced 7-ketone, analogously as described in Example 1 inconnection with the preparation of the starting material in stages(D)-(F), was reduced with lithium tri-tert.-butoxyaluminohydride to the17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androsten-7β-ol,epoxidized with tert.-butyl hydroperoxide in the presence ofvanadium(IV) oxide acetylacetonate to17β-acetoxy-3β-benzoyloxy-5,6β-epoxy-15β,16β-methylene-5β-androstan-7β-ol,and then reacted with triphenylphosphine in carbon tetrachloride andpyridine to the17β-acetoxy-3β-benzoyloxy-7α-chloro-5,6β-epoxy-15.beta.,16β-methylene-5β-androstane,mp 201.5°-206° C. (diisopropyl ether-acetone).

EXAMPLE 3

Analogously to Example 2, 13.5 g of3β,17β-dibenzoyloxy-7α-chloro-5,6β-epoxy-15β,16.beta.-methylene-5β-androstaneis reacted in 130 ml of acetic acid and 130 ml of propan-2-ol with 49.5g of zinc dust and worked up. Chromatography on silica gel yields 8.8 gof 3β,17β-dibenzoyloxy-15β,16β-methylene-5β-androst-6-en-5-ol, mp223°-225° C. (acetone-diisopropyl ether).

Preparation of starting material

(A) A solution of 21 g of3β-hydroxy-15β,16β-methylene-5-androsten-18-one in 210 ml oftetrahydrofuran was stirred with 21 g of lithiumtri-tert.-butoxyaluminohydride for 1 hour at room temperature. Themixture was then diluted with diethyl ether, washed with 2N sulfuricacid and water, dired, and evaporated, thus obtaining 19 g of15β,16β-methylene-5-androstene-3β,17β-diol, used without furtherpurification in the subsequent stage.

(B) 15β,16β-Methylene-5-androstene-3β,17β-diol, analogously to Example2, as described in the preparation of the starting material, was reactedwith benzoyl chloride to3β,17β-dibenzoyloxy-15β,16β-methylene-5-androstene, oxidized withtert.-butyl chromate to3β,17β-dibenzoyloxy-15β,16β-methylene-5-androsten-7-one, and reducedwith lithium tri-tert.-butoxyaluminohydride to3β,17β-dibenzoyloxy-15β,16β-methylene-5-androsten-7.beta.-ol; thelast-mentioned compound was reacted with tert.-butyl hydroperoxide to3β,17β-dibenzoyloxy-5,6β-epoxy-15β,16β-methylene-5β-androstane andconverted with triphenylphosphine in carbon tetrachloride and pyridineinto3β,17β-dibenzoyloxy-7α-chloro-5,6β-epoxy-15β,16.beta.-methylene-5β-androstane.The product obtained after chromatography and recrystallization fromdiisopropyl ether-acetone melted at 197.5°-198.5° C.

EXAMPLE 4

3.0 g of17β-acetoxy-3β-benzoyloxy-7α-chloro-5,6β-epoxy-5.beta.-androstane isreacted analogously to Example 2 in 30 ml of acetic acid and 30 ml ofpropan-2-ol with 9 g of zinc dust and worked up. Yield: 2.8 g of17β-acetoxy-3β-benzoyloxy-5β-androst-6-en-5-ol, mp 180°-185° C.

Preparation of starting material

Analogously to Example 2(A)-(C), 3β-hydroxy-5-androsten-17-one wasconverted into 17β-acetoxy-3β-benzoyloxy-5-androstene. Analogously toExample 2(D), 17β-acetoxy-3β-benzoyloxy-5-androsten-7-one was producedfrom this product with tert.-butyl chromate. Reducing, epoxidizing, andchlorination reactions were carried out analogously to Example 1(D)-(F),thus obtaining17β-acetoxy-3β-benzoyloxy-7α-chloro-5,6β-epoxy-5.beta.-androstane, mp173°-175.5° C. after chromatography on silica gel.

EXAMPLE 5

300 mg of3β-acetoxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β,17α-pregnane-21,17-carbolactoneis stirred in 15 ml of propan-2-ol and 15 ml of acetic acid with 900 mgof zinc dust for 2 hours at 80° C. After filtration, the mixture isdiluted with methylene chloride and washed with sodium bicarbonatesolution and water, dried over magnesium sulfate, and evaporated undervacuum. The residue is purified by preparative thin-layerchromatography, yielding 150 mg of3β-acetoxy-5-hydroxy-5β,17α-pregn-6-ene-21.17-carbolactone, mp 209°-211°C.

Preparation of starting material

(A) A suspension of 20 g of3β-hydroxy-15β,16β-methylene-5-androsten-17-one in 400 ml of benzene wasdried azeotropically by removing 40 ml of liquid by distillation, andcombined at room temperature with 50 ml of distilled dihydropyran and250 ml of toluenesulfonic acid. After 1 hour at room temperature, 4 mlof pyridine was added, the mixture was diluted with diethyl ether,washed with sodium bicarbonate solution and water, and dried overmagnesium sulfate. The crude product obtained after evaporation wasextracted by boiling with methanol, filtered, and dried, yielding 22.4 gof 15β,16β-methylene-3β-(tetrahydropyran-2-yloxy)-5-androsten-17-one, mp175°-178° C.

(B) 22 g of15β,16β-methylene-3β-(tetrahydropyran-2-yloxy)-5-androsten-17-one wasdissolved in 400 ml of tetrahydrofuran; under ice cooling and an argonatmosphere, 65 g of potassium ethylate was added and under agitation asolution of 44 ml of propargyl alcohol in 88 ml of tetrahydrofuran wasadded dropwise to this suspension. The mixture was then stirred underargon for 4 hours at room temperature. This solution was poured into 5 lof saturated sodium chloride solution and neutralized with acetic acid.The precipitate was filtered off and taken up in methylene chloride. Thesolution was washed, dried, and evaporated. The resultant crude productwas triturated with ethyl acetate, thus obtaining 23 g of17α-(3-hydroxy-1-propynyl)-15β,16β-methylene-3β-(tetrahydropyran-2-yloxy)-5-androsten-17β-ol,mp 193°-196° C.

(C) A solution of 22 g of17α-(3-hydroxy-1-propynyl)-15β,16β-methylene-3β-(tetrahydropyran-2-yloxy)-5-androsten-17β-olin 1.3 l of methanol was combined with 3 spoonfuls of Raney nickel andshaken under a hydrogen atmosphere, during which step 2.27 l of hydrogenwas absorbed. The catalyst was then vacuum-filtered, the filtrateevaporated under vacuum, and the residue recrystallized from ethylacetate, thus obtaining 16.75 g of17α-(3-hydroxypropyl)-15β,16β-methylene-3β-(tetrahydropyran-2-yloxy)-5-androsten-17β-ol,mp 156°-160° C.

(D) A solution of 15 g of17α-(3-hydroxypropyl)-15β,16β-methylene-3β-(tetrahydropyran-2-yloxy)-5-androsten-17β-olin 1.2 l of dimethylformamide was combined with 48 g of pyridiniumdichromate and stirred for 3 hours at room temperature. The mixture wasthen poured into saturated sodium chloride solution, the precipitate wasfiltered off and washed with methanol. The resultant crude product wasrecrystallized from methanol, thus obtaining 14.3 g of3β-(tetrahydropyran-2-yloxy)-15β,16β-methylene-17α-pregn-5-ene-21,17-carbolactone,mp 218°-220° C.

(E) 14.3 g of3β-(tetrahydropyran-2-yloxy)-15β,16β-methylene-17α-pregn-5-ene-21,17-carbolactonewas dissolved in 250 ml of methanol and 150 ml of methylene chloride, 2ml of 3N hydrochloric acid was added thereto, and the mixture wasstirred for 2 hours at room temperature. Then the mixture was evaporatedunder vacuum, the residue dissolved in methylene chloride and washedneutral. The crude product, thus formed after evaporation, was extractedby boiling with methanol, thus obtaining 11.6 g of3β-hydroxy-15β,16β-methylene-17α-pregn-5-ene-21,17-carbolactone, mp216°-223° C.

(F) 750 mg of3β-hydroxy-15β,16β-methylene-17α-pregn-5-ene-21,17-carbolactone wasdissolved in 10 ml of pyridine, combined with 10 ml of acetic anhydride,and heated for 1 hour on a steam bath. The mixture was then introducedinto ice water, the precipitate filtered off and dried under vacuum. Theresultant crude product was purified by gradient chromatography, thusobtaining 683 mg of3β-acetoxy-15β,16β-methylene-17α-pregn-5-ene-21,17-carbolactone, mp224°-226° C.

(G) The thus-produced3β-acetoxy-15β,16β-methylene-17α-pregn-5-ene-21,17-carbolactone wasconverted analogously to Example 1(C)-(F) into3β-acetoxy-7α-chloro-5,6-epoxy-15β,16β-methylene-5.beta.,7α-pregnane-21,17-carbolactone.

EXAMPLE 6

A suspension is prepared from 61 g of3β-(tetrahydropyran-2-yloxy)-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β,17α-pregnane-21,17-carbolactonein 400 ml of tetrahydrofuran, 400 ml of acetic acid, and 160 ml ofwater. The suspension is combined within 45 minutes with 150 g of zincdust in 3 portions and heated for 4.5 hours to 70° C. After cooling, themixture is stirred into ice water, neutralized with sodium bicarbonate,and extracted with methylene chloride. The extract is dried, afterwashing with water, over magnesium sulfate and evaporated under vacuum.The residue is chromatographed on silica gel, thus obtaining 37.9 g of3β,5-dihydroxy-15β,16β-methylene-5β,17α-pregn-6-ene-21,17-carbolactone,mp 237°-238° C.

Preparation of starting material

Analogously to Example 1(C)-(F),3β-(tetrahydropyran-2-yloxy)-15β,16β-methylene-17α-pregn-5-ene-21,17-carbolactonewas converted into3β-(tetrahydropyran-2-yloxy)-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β,17α-pregnane-b21,17-carbolactone.

What is claimed is:
 1. A process for preparing a 5β-hydroxy-Δ⁶ -steroidof the general formula ##STR4## wherein R¹ is hydrogen, acyl, loweralkyl, or tetrahydropyranyl andR², R³ jointly are methylene and X isoxygen, or ##STR5## comprising treating the corresponding7α-chloro-5β,6β-epoxy steroid with a lower aliphatic carboxylic acid ora dilute mineral acid, in an inert solvent, in the presence of metalliczinc at a temperature of between room temperature and 100° C.
 2. A5β-hydroxy-Δ⁶ -steroid of the formula ##STR6## wherein X is oxygen, or##STR7## 3.3β-Acetoxy-5-hydroxy-15β,16β-methylene-5β-androst-6-en-17-one a compoundof claim
 2. 4. A process of claim 1, wherein the treatment temperatureis 40°-70° C. 5.3β,5-Dihydroxy-15β,16β-methylene-5β,17α-pregn-6-ene-21,17-carbolactone acompound of claim 2.